title: Design of novel melatonin analogs for the reduction of intraocular pressure in normotensive rabbits.
abstract: Melatonin, the MT(2) melatonin receptor agonist IIK7 [N-butanoyl-2-(2-methoxy-6H-isoindolo[2,1-a]indol-11-yl)ethanamine], and the putative MT(3) melatonin receptor agonist 5-MCA-NAT [5-methoxycarbonylamino-N-acetyltryptamine] have previously been shown to reduce intraocular pressure (IOP) in ocular normotensive rabbits. To gain a better understanding of the structure-activity relationship of compounds that activate MT(2) and MT(3) receptors mediating reductions in IOP, novel melatonin analogs with rationally varied substitutions were synthesized and tested for their effects on IOP in ocular normotensive rabbits (n = 160). All synthesized melatonin analogs reduced IOP. The best-effect lowering IOP was obtained with the analogs INS48848 [methyl-1-methylene-2,3,4,9-tetrahydro-1H-carbazol-6-ylcarbamate], INS48862 [methyl-2-bromo-3-(2-ethanamidoethyl)-1H-indol-5-ylcarbamate], and INS48852 [(E)-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-3-phenylprop-2-enamide]. These compounds produced dose-dependent decreases in IOP that were maximal at 0.1 mM (total dose of 0.259 μg for INS48848, 0.354 μg for INS48862, and 0.320 μg for INS48852) and 1 mM (total dose of 2.59 μg for INS48848, 3.54 μg for INS48862, and 3.20 μg for INS48852), with maximal reductions of 36.0 ± 4.0, 24.0 ± 1.5, and 30.0 ± 1.5% for INS48848, INS48862, and INS48852, respectively. Studies using melatonin receptor antagonists (luzindole, prazosin, and DH97 [N-pentanoyl-2-benzyltryptamine]) indicated that INS48862 and INS48852 activate preferentially a MT(2) melatonin receptor and suggest that INS48848 may act mainly via a MT(3) receptor. The most effective compounds were also well tolerated in a battery of standard ocular surface irritation studies. The implication of these findings to the design of novel drugs to treat ocular hypertension is discussed.
authors.affiliation: Departamento Bioquímica, Escuela Universitaria de Óptica, Universidad Complutense Madrid, C/Arcos de Jalón 118, 28037 Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Alarma-Estrany
authors.forename: Ana
authors.initials: A
authors.lastname: Guzman-Aranguez
authors.forename: Fernando
authors.initials: F
authors.lastname: Huete
authors.forename: Assumpta
authors.initials: A
authors.lastname: Peral
authors.forename: Robert
authors.initials: R
authors.lastname: Plourde
authors.forename: Teresa
authors.initials: T
authors.lastname: Pelaez
authors.forename: Benjamin
authors.initials: B
authors.lastname: Yerxa
authors.forename: Jesús
authors.initials: J
authors.lastname: Pintor
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005123:Eye / Q000378:metabolism; D005901:Glaucoma / Q000188:drug therapy; D007429:Intraocular Pressure / Q000187:drug effects*; D054833:Isoindoles / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D008550:Melatonin / Q000031:analogs & derivatives*; D009798:Ocular Hypertension / Q000188:drug therapy*; D011817:Rabbits; D044123:Receptor, Melatonin, MT2 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D044094:Receptors, Melatonin / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D013997:Time Factors; D014363:Tryptamines / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity
chemical_list: C413586:5-methoxycarbonylamino-N-acetyltryptamine; C121417:IIK7; D054833:Isoindoles; C408803:N-pentanoyl-2-benzyltryptamine; D044123:Receptor, Melatonin, MT2; D044094:Receptors, Melatonin; D014363:Tryptamines; C057154:luzindole; D008550:Melatonin